Phosphatase of regenerating liver-3 is regulated by signal transducer and activator of transcription 3 in acute myeloid leukemia

Abstract Abstract 4859 Objectives: Signal transducer and activator of transcription 5 (STAT5) protein is one of the concernful part of STATs families. The constitutive STATs activation has been especially showed in transformation by fusion genes in leukemias. Methods: In this study, we aimed to investigate whether the genetic polymorphisms in the STAT5 gene are associated with the treatment outcomes of Ara-C-based chemotherapy regimens in Acute Myeloid Leukemia (AML) patients. 152 AML patients in a Chinese sample were enrolled in our study. Peripheral blood samples were analyzed by matrix assisted laser desorption ionisation-time of flight mass spectrometry (MALDI-TOF-MS). Results: The results showed that the frequencies of the T/T genotype in rs2293157 and rs1135669 were higher in unfavorable and intermediate group respectively (P=0.023 and P=0.033). The frequency of patients with T/T genotype of rs1135669 was significantly higher in complete remission (CR) group. Conclusions: We concluded that the T/T genotype of rs1135669 might be an important marker for therapeutic efficiency of Ara-C-based chemotherapy in AML patients, especially in Chinese population. Disclosures: No relevant conflicts of interest to declare.

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Constitutive Stat3, Tyr705, and Ser727 phosphorylation in acute myeloid leukemia cells caused by the autocrine secretion of interleukin-6

Blood ◽

10.1182/blood.v95.12.3765 ◽

2000 ◽

Vol 95 (12) ◽

pp. 3765-3770 ◽

Cited By ~ 118

Author(s):

Jan-Jacob Schuringa ◽

Albertus T. J. Wierenga ◽

Wiebe Kruijer ◽

Edo Vellenga

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cytokine Signaling ◽

Mobility Shift ◽

Activation Patterns ◽

Stat3 Phosphorylation ◽

Acute Myeloid Leukemia Cells ◽

Mobility Shift Assay ◽

Transcription 3 ◽

Acute Myeloid

Abstract To explore the activation patterns of signal transducer and activator of transcription 3 (Stat3) in acute myeloid leukemia (AML), we examined whether the phosphorylation of tyrosine705 (Tyr705) and serine727 (Ser727) residues was abnormally regulated in cells from patients with AML. In 5 of 20 (25%) patients with AML, Stat3 was constitutively phosphorylated on Tyr705 and Ser727, which were not further up-regulated by treatment with IL-6. Furthermore, Stat3 was constitutively bound to the IRE response element in these cells as determined by electrophoretic mobility shift assay, and stimulation with IL-6 did not result in increased DNA binding. Interestingly, AML cells with constitutive Stat3 activation also secreted high levels of IL-6 protein. Treating these AML cells with anti-IL-6 resulted in restored IL-6–inducible Stat3 phosphorylation on both Tyr705 and Ser727 with low or undetectable basal phosphorylation levels in unstimulated cells. In contrast, treatment with anti-IL-1 did not result in altered Stat3 phosphorylation patterns. The constitutive IL-6 expression was associated with elevated levels of suppressor of cytokine signaling-1 (SOCS-1) and SOCS-3 mRNA expression, which were not down-regulated by anti-IL-6. These data indicate that the constitutive Stat3 activation in the investigated AML blasts is caused by high IL-6 secretion levels, thus stimulating the Jak/Stat pathway in an autocrine manner, a paracrine manner, or both.

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Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival

Blood ◽

10.1182/blood.v99.1.252 ◽

2002 ◽

Vol 99 (1) ◽

pp. 252-257 ◽

Cited By ~ 118

Author(s):

Mustafa Benekli ◽

Zheng Xia ◽

Kathleen A. Donohue ◽

Laurie A. Ford ◽

Lynda A. Pixley ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Treatment Outcome ◽

Myeloid Leukemia ◽

Disease Free Survival ◽

Signal Transducer ◽

Free Survival ◽

Stat Proteins ◽

Disease Free ◽

Acute Myeloid

Signal transducer and activator of transcription (STAT) proteins are involved in hematopoietic cytokine receptor signaling pathways that regulate cell proliferation, differentiation, and survival. STATs are dysregulated in acute myeloid leukemia (AML); mechanisms of dysregulation include constitutive activation and truncation of the C-terminal transactivation domain; the latter results in a β isoform that has a trans-dominant negative effect on gene induction mediated by the full-length STATα form. It was hypothesized that constitutive STAT activity might correlate with unfavorable treatment outcome in AML. Pretreatment bone marrow samples from 63 adult patients with AML were analyzed by electrophoretic mobility shift assay for the presence of STAT DNA-binding activity. Isoforms and relative levels of STAT proteins were determined by immunoblotting. Constitutive STAT3 activity was detected in samples from 28 (44%) patients. Pretreatment clinical characteristics, expression of STATα/β isoforms, and treatment regimens did not differ significantly between patients with and without constitutive STAT3 activity. Disease-free survival (DFS) was significantly shorter in patients with than in patients without constitutive STAT3 activity (median 8.7 vs 20.6 months;P = .01). Overall survival did not differ significantly. The subgroup of patients with constitutive STAT3 activity and the STAT3β isoform had the shortest DFS (P = .006) and shorter overall survival (P = .049) than all other patients. Whether adverse treatment outcome is attributable to constitutive STAT activity itself or to a process that leads to constitutive STAT activity remains to be determined. This is the first demonstration of a prognostic significance for STAT proteins in a malignancy.

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Comprehensive Analysis of the Expression and Prognosis for Signal Transducer and Activator of Transcription Family of Genes in Acute Myeloid Leukemia

10.21203/rs.3.rs-832374/v1 ◽

2021 ◽

Author(s):

Tong Qin ◽

Yunli Shao ◽

Hongmian Zhao

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Predictive Biomarker ◽

Signal Transducer ◽

Lasso Regression ◽

Expression Levels ◽

Normal Tissues ◽

Immunotherapy Target ◽

Selection Operator ◽

Acute Myeloid

Abstract BackgroundIn recent years, it has become clear that signal transducer and activator of transcription (STAT) family of genes play an important role in cancer. However, the expression level, genetic variation, molecular mechanism, and biological function of different STATs in acute myeloid leukemia (AML) and its relationship with prognosis and immune infiltration in patients with AML have not been fully elucidated.ResultsWe found that the expression levels of STAT1, STAT2, STAT4, and STAT6 were higher in AML than in normal tissues, whereas the expression levels of STAT3, STAT5A, and STAT5B were lower in the former than in the latter. Survival analysis revealed that high transcription level of STAT6 was associated with low overall survival (OS) in patients with AML. Conversely, high STAT5B level predicted superior OS in these patients. Cox multivariate analysis as well as least absolute shrinkage and selection operator (LASSO) regression screening showed that STAT5B expression is a good independent prognostic factor of OS. The functions of STAT5B are mainly related to the occurrence, development and microenvironment of AML. We also discovered that the expression of STAT5B was significantly correlated with immune infiltrates in AML.ConclusionsSTAT5B may be used as a novel predictive biomarker and immunotherapy target for AML patients.

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